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Individuals with type 1 diabetes (T1D) frequently fail to achieve glycemic goals and have excess cardiovascular risk and premature death. Adjunctive agents may play a role in reducing morbidity, mortality, and the adverse sequelae of insulin treatment. A surge in type 2 diabetes drug development has revealed agents with benefits beyond glucose lowering, including cardiovascular risk reduction. Could these benefits translate to T1D? Specific trials for T1D demonstrate substantial hemoglobin (Hb)A1c reductions with sodium glucose cotransporter inhibitors (SGLTis) and glucagon-like peptide (GLP)1 agonists, and modest improvements with metformin, dipeptidyl peptidase-4 inhibitor (DPP4i), and pramlintide. Studies exploring cardiovascular risk reduction are warranted. This review synthesizes the emerging literature for researchers and clinicians treating people with T1D. Challenges in T1D research are discussed.

BACKGROUND Limited studies have compared outcomes between emerging adults with type 1 diabetes mellitus (T1D) attending a diabetes transition support programme using multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII). AIMS To assess glycaemic control and service utilisation in emerging adults with T1D on MDI or CSII attending a young adult diabetes clinic (YAC). METHODS A retrospective cohort analysis was conducted from January 2013 to December 2015. Data collected included clinic visits per-year, after-hours mobile phone use, diabetic ketoacidosis (DKA) admissions and all HbA1c levels. Independent t-test was used to compare continuous variables whilst Pearson's chi-squared test was used for categorical variables. Linear mixed effects models explored mean changes in HbA1c levels over time. RESULTS Over 3 years, 318 youth with T1D (176 MDI, 121 CSII, 21 switched from MDI to CSII) attended our YAC. Aggregated mean HbA1c levels remained similar between modalities (CSII 9.1% vs. MDI 9.3%, p = 0.23), however, mean change in HbA1c at 3 years was significantly increased in CSII users at 0.55% (95% CI 0.15% to 0.95%, p

BACKGROUND Insulin resistance is an under-recognised metabolic defect and cardiovascular risk factor in Type 1 diabetes. Whether metformin improves hepatic, muscle or adipose tissue insulin sensitivity has not been studied in adults with Type 1 diabetes. We initiated the INTIMET study (INsulin resistance in Type 1 diabetes managed with METformin), a double-blind randomised, placebo-controlled trial to measure the effect of metformin on tissue-specific insulin resistance in adults with Type 1 diabetes. METHODS We will study 40 adults aged 20-55 years with Type 1 diabetes (HbA1c ≤ 80 mmol/mol [9.5%], fasting C-peptide

Background: Insulin resistance is an under-recognised cardiovascular risk factor in type 1 diabetes (T1D). Individuals with T1D exhibit insulin resistance relative to those without diabetes. In T1D, tissue-specific insulin resistance (muscle, hepatic, adipose) is likely to partly drive increased cardiovascular risk. Adjunctive metformin improves muscle insulin sensitivity in T1D adolescents, but factors that predict responsiveness remain unknown.Objective: To report the rationale and design of the INTIMET study, a double-blind randomised, placebo-controlled trial of metformin in T1D.Methods: Forty adults aged 20-50 years with T1D, and 20 age- gender- and BMI- matched non-diabetic controls will be studied. T1D inclusion criteria are diagnosis > 10 years, HbA1c 9.5% and fasting C-peptide < 0.3nmol/L. Liver and muscle insulin sensitivity will be determined by the 2-stage hyperinsulinemic (20 and 60 mUm2)-euglycemic (5.5 mmol/L) clamp method with deuterated glucose. Subjects with T1D will be randomised to metformin extended-release 1500mg/d or matched placebo for 26 weeks. The primary endpoint is the change in hepatic insulin sensitivity, measured by suppression of endogenous glucose production (EGP) with the low-dose insulin clamp. Secondary endpoints include change in muscle and adipose tissue insulin sensitivity, arterial stiffness, HbA1c, glucose variability, frequency of hypoglycemia, insulin dose, anthropometry, body composition, lipid profile, liver fat and stiffness. Conclusion: The INTIMET study will quantify muscle, liver and adipose insulin-resistance in T1D, determine whether metformin is effective in improving insulin resistance in T1D and identify factors that predict metformin-responsiveness. The trial is registered (Australian New Zealand Clinical Trial Registry, ACTRN12619001440112) and is actively recruiting in Sydney, Australia.

Background Young people with type 1 diabetes are at increased risk of mental disorders. Whereas treatment need is high, difficulty recruiting young people with type 1 diabetes into psychosocial studies complicates development, testing and dissemination of these interventions. Objective Interviews with young adults with type 1 diabetes were conducted to examine attitudes towards mental health and mental health research, including barriers and motivators to participation in mental health studies and preferred sources of mental health support. The interviews were audio‐taped, transcribed and evaluated via thematic analysis. Setting and participants Young adults with type 1 diabetes were recruited via social media channels of 3 advocacy organizations. A total of 31 young adults (26 females and 5 males) with an average age of 22 years were interviewed between October 2015 and January 2016. Results Participants were largely unaware of their increased vulnerability to common mental health problems and knew little about mental health research. Major barriers to participation included perceived stigma and lifestyle issues and low levels of trust in researchers. Opportunities to connect with peers and help others were described as key motivators. Psychological distress was considered normal within the context of diabetes. A need for some level of human contact in receiving psychosocial support was expressed. Discussion and conclusion Findings provide valuable insights into the complex dynamics of engaging young adults with type 1 diabetes in mental health studies. Interviewees provided practical suggestions to assist investigation and delivery of psychosocial interventions for this vulnerable group.

Aims and Objectives: The aim of this paper was to evaluate the impact of phone support on sick day management of young people with type 1 diabetes.Method: Qualitative exploratory study to understan...

We read with great interest that Braffett et al. (1) report an association between insulin dose and adverse cardiometabolic profiles using 30 years of follow-up data from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. Intensive diabetes treatment necessitating increased insulin doses became the accepted standard of care in type 1 diabetes after the DCCT/EDIC trial demonstrated cardiovascular risk benefit (mean ± SD 0.71 ± 0.21 vs. 0.65 ± 0.21 units/kg/day in the intensive vs. conventional treatment group; P = 0.0001). We support the authors’ emphasis that this association is somewhat driven by insulin-related weight gain, especially in males. The report …

Background Healthcare professional (HCP) time supporting insulin pump therapy (IPT) has not been documented, yet it is important in planning and allocating resources for effective care. Aim This study aims to determine HCP time spent in IPT patient care to inform resource planning for optimal IPT delivery. Methods Twenty-four Australian adult IPT-experienced institutions (14 government funded, seven private, three both) collected data between April 2012 and January 2013 prospectively, including: patient demographics, HCP classification, purpose of HCP–patient interaction, interaction mode and HCP time with the patient. A subset of patients was tracked from pre-pump education until stable on IPT. Results Data on 2577 HCP-adult patient interactions (62% face-to-face, 29% remote, 9% administrative) were collected over 12.2 ± 6.4 weeks for 895 patients; age 35.4 ± 14.2 years; 67% female; 99% type 1 diabetes, representing 25% of all IPT patients of the institutions. Time (hours) spent on IPT interactions per centre per week were: nurses 5.4 ± 2.8, dietitians 0.4 ± 0.2 and doctors 1.0 ± 0.5. IPT starts accounted for 48% of IPT interaction time. The percentage of available diabetes clinic time spent on outpatient IPT interactions was 20.4%, 4.6% and 2.7% for nurses, dietitians and doctors respectively. Fifteen patients tracked from pre-pump to stabilisation over 11.8 ± 4.5 weeks, required a median (range) of 9.2 (3.0–20.9), 2.4 (0.5–6.0) and 1.8 (0.5–5.4) hours per patient from nurses, dietitians and doctors respectively. Conclusions IPT patient care represents a substantial investment in HCP time, particularly for nurses. Funding models for IPT care need urgent review to ensure this now mainstream therapy integrates well into healthcare resources.

To determine whether cardiovascular outcomes in type 2 diabetes (T2D) differ according to ethnicity, and whether ethnicity influences the effect of gender on these outcomes in Caucasians, East-Southeast-Asians, Middle-Easterners, South-Asians and Pacific-Islanders.We compared demographics, HbA1c, lipid profile, renal function markers, and prevalence of macrovascular and microvascular complications between ethnic groups. Cross-sectional data was prospectively collected from 204 consecutive patients at Westmead Hospital's T2D clinic from April-October 2015. Univariate analysis was performed using chi-squared test for categorical data, and Mann-Whitney-U or Kruskal-Wallis test for continuous data.Compared to Caucasians, South-Asians were diagnosed younger, were currently younger, had lower body-mass-index (BMI) and better renal function but higher rates of non-ST-elevation myocardial infarction (STEMI, 21.7% versus 3.5%, p0.05). East-Southeast-Asians had lower BMI but more nephropathy than Caucasians (59% versus 39%, p0.05). East-Southeast-Asian males had fewer CVD than Caucasians, but this protection was absent in East-Southeast-Asian females. Middle-Easterners had more non-STEMI than Caucasians (5.3% vs 3.5%, p0.05). Middle-Eastern females were not at lower CVD risk than males. Caucasians had most PVD (20% versus 6%, p0.05).Ethnicity influences rates of diabetes-related complications. Female CVD protection is altered in some groups. Ethnicity should be considered in assessing CVD and complications risk.

Multiple guidelines have been published over the last few years for the diagnosis and management of cystic fibrosis (CF) and cystic fibrosis related diabetes (CFRD), although some of the recommendations are based on extrapolation from other forms of diabetes and/or expert opinions. This document seeks to combine the guidelines to provide an Australian approach to the management of CFRD and establish the guidelines within the Australian CF Standards of Care. It is intended that this document will provide assistance to doctors, nurses, dietitians, physiotherapists, diabetes educators and CF patients concerning the issues surrounding CFRD, and will be reviewed and updated in 2016.

Whilst initial rates of insulin independence following islet transplantation are encouraging, long-term function using the Edmonton Protocol remains a concern. The aim of this single-arm, multicenter study was to evaluate an immunosuppressive protocol of initial antithymocyte globulin (ATG), tacrolimus and mycophenolate mofetil (MMF) followed by switching to sirolimus and MMF. Islets were cultured for 24 h prior to transplantation. The primary end-point was an HbA1c of7% and cessation of severe hypoglycemia. Seventeen recipients were followed for ≥ 12 months. Nine islet preparations were transported interstate for transplantation. Similar outcomes were achieved at all three centers. Fourteen of the 17 (82%) recipients achieved the primary end-point. Nine (53%) recipients achieved insulin independence for a median of 26 months (range 7-39 months) and 6 (35%) remain insulin independent. All recipients were C-peptide positive for at least 3 months. All subjects with unstimulated C-peptide0.2 nmol/L had cessation of severe hypoglycemia. Nine of the 17 recipients tolerated switching from tacrolimus to sirolimus with similar graft outcomes. There was a small but significant reduction in renal function in the first 12 months. The combination of islet culture, ATG, tacrolimus and MMF is a viable alternative for islet transplantation.

Following the introduction of highly active antiretroviral therapy, an expanding cohort of adolescents with perinatally acquired HIV (PaHIV) is surviving and emerging from pediatric services with complex transition health care requirements. Transfer from pediatric to adult services has been associated with poorer health outcomes in other chronic diseases. Young people with HIV have the additional burden of stigma, secrecy, and the risk of transmitting HIV to partners and offspring. Maintaining engagement in health care during adolescence is critical. We compare reported satisfaction surveys of health care experiences and preferences of young people with PaHIV attending a U.K. transition outpatient service with young people attending a young persons' diabetes transition service in Australia. All 21 patients in the United Kingdom and 39 young people approached in Australia agreed to participate. The median age for both groups was 19 years, 67% of the PaHIV group were black African and 74% of diabetic group white Australian. Ninety-five percent (18/19) of those with PaHIV and 87% (34/39) with diabetes felt their transition was an easy process. Sixty-eight percent (13/19) of young people with PaHIV and 72% (28/39) of diabetic patients felt moving to their current service had a positive effect on their health. Being treated as an individual, comprehensive management explanations and encouragement to develop independence were cited as "strongly important" by over three quarters of participants with PaHIV. This service evaluation illustrates that careful transition can be a positive event for young people with PaHIV, comparable to that of a well-established diabetes services.

Diabet. Med. 28, 1001–1004 (2011) Abstract Aims To determine if access to mobile phone support for sick-day management is associated with reduced hospital admissions with diabetic ketoacidosis in young adults aged 15–25 with Type 1 diabetes. Methods This was an observational study with data collected prospectively from January 2005 to December 2008. A mobile phone support service for sick-day management began in May 2005. Data from clinic attendees (group 1), including age, sex, diabetes duration, referral age, insulin therapy delivery, clinic attendance and HbA1c, were compared with clinic attendees with diabetic ketosis accessing sick-day management phone support (group 2), clinic attendees not accessing phone support and admitted with diabetic ketoacidosis (group 3) and non-clinic attendees admitted with diabetic ketoacidosis (group 4). Results Age was similar in all groups. Patients in group 3 had significantly shorter duration of diabetes (6.8 ± 3.1 years) than groups 1 or 2 (10.1 and 9.8 years, respectively). Diabetes control was poor in all presentations of diabetic ketoacidosis (groups 2–4, HbA1c > 97 mmol/mol, > 11%) and was significantly higher than clinic attendees without ketosis (HbA1c 70 mmol/mol, 8.6%; P

Healthcare professional (HCP) time supporting insulin pump therapy (IPT) has not been documented, yet it is important in planning and allocating resources for effective care.This study aims to determine HCP time spent in IPT patient care to inform resource planning for optimal IPT delivery.Twenty-four Australian adult IPT-experienced institutions (14 government funded, seven private, three both) collected data between April 2012 and January 2013 prospectively, including: patient demographics, HCP classification, purpose of HCP-patient interaction, interaction mode and HCP time with the patient. A subset of patients was tracked from pre-pump education until stable on IPT.Data on 2577 HCP-adult patient interactions (62% face-to-face, 29% remote, 9% administrative) were collected over 12.2 ± 6.4 weeks for 895 patients; age 35.4 ± 14.2 years; 67% female; 99% type 1 diabetes, representing 25% of all IPT patients of the institutions. Time (hours) spent on IPT interactions per centre per week were: nurses 5.4 ± 2.8, dietitians 0.4 ± 0.2 and doctors 1.0 ± 0.5. IPT starts accounted for 48% of IPT interaction time. The percentage of available diabetes clinic time spent on outpatient IPT interactions was 20.4%, 4.6% and 2.7% for nurses, dietitians and doctors respectively. Fifteen patients tracked from pre-pump to stabilisation over 11.8 ± 4.5 weeks, required a median (range) of 9.2 (3.0-20.9), 2.4 (0.5-6.0) and 1.8 (0.5-5.4) hours per patient from nurses, dietitians and doctors respectively.IPT patient care represents a substantial investment in HCP time, particularly for nurses. Funding models for IPT care need urgent review to ensure this now mainstream therapy integrates well into healthcare resources.

Background The pathophysiological mechanism of diabetes mellitus in the presence of the 3243 A-G tRNALEU(UR) mitochondrial DNA mutation is thought to result from deficient insulin secretion. However, few subjects with normal glucose tolerance have been studied to determine the sequence of events resulting in the development of diabetes mellitus. Aim To determine whether abnormalities of insulin sensitivity, insulin secretion or glucose effectiveness are present in non-diabetic subjects with the 3243 A-G tRNALEU(UUR) mitochondrial DNA mutation. Methods Twelve non-diabetic subjects with the mutation were compared with 12 controls, matched for age and anthropometric parameters, using both oral and intravenous glucose tolerance tests, the latter with Minimal Model analysis. Results Following an oral glucose load we found significantly higher blood glucose levels at 90 min and 120 min and significantly higher insulin levels at 120 min and 180 min in non-diabetic subjects with the mutation but no difference in the insulinogenic indices at 30 min and 180 min. From the intravenous glucose tolerance test there was no difference in overall glucose tolerance, insulin sensitivity, first- or second-phase insulin secretion, proinsulin secretion or glucose effectiveness. Insulin-independent glucose disposal was increased in subjects with lower insulin sensitivity and declined with increasing age in subjects with the mutation but not in controls. Conclusions While there appear to be subtle defects of glucose handling in non-diabetic subjects with the 3243 mutation, these could not be explained by differences in insulin sensitivity or secretion. Diabet. Med. 18, 381–387 (2001)

Two types of retinopathy, diabetic and pigmentary, may be seen in subjects with maternal inheritance diabetes and deafness. The potential for interactions between the two retinopathies has not been explored. The mitochondrial mutation may affect development of diabetic retinopathy in subjects with MIDD by altering normal pathways of glucose metabolism. We identified five unrelated MIDD kindreds with 61 living maternal line family members. Twenty-three of the family members, 12 with diabetes mellitus and 11 without volunteered to be studied. Subjects were graded for severity of diabetic retinopathy and presence or absence of pigmentary retinopathy after slit lamp biomicroscopy, retinal photography of seven standard fields and fluorescein angiography. Blood was taken, in the fasted state, from MIDD subjects (duration of diabetes 17.0+/-6.9 yr) and non-diabetic subjects with the mutation, for assay of sorbitol and glucose and values compared with diabetic and non-diabetic control subjects without the mutation. Diabetic retinopathy was absent in 9/12 subjects (75%), with 3 having mild non-proliferative retinopathy. No one had cataract. Red blood cell sorbitol levels, adjusted for ambient blood glucose, were significantly lower in MIDD subjects compared with diabetic subjects (1.16+/-0.5 cf. 2.03+/-1.1, x 10(-3) g mmol(-1), p=0.04). Pigmentary retinopathy was present in 15 of 23 subjects, of whom 13 had some abnormality of glucose tolerance. Abnormal glucose tolerance was strongly associated with the development of pigmentary retinopathy (odds ratio 19.5, p=0.008). In conclusion, there appears to be a decreased prevalence of diabetic retinopathy and cataract in MIDD, which we propose is due to reduced glucose metabolism by the polyol pathway. Abnormal glucose tolerance increases the clinical expression of pigmentary retinopathy in subjects with a mitochondrial genome mutation. A greater understanding of the metabolic effects of mitochondrial DNA mutations has the potential to give insight into the mechanisms of diabetic retinopathy and other complications of diabetes mellitus.

To determine if access to mobile phone support for sick-day management is associated with reduced hospital admissions with diabetic ketoacidosis in young adults aged 15-25 with Type 1 diabetes.This was an observational study with data collected prospectively from January 2005 to December 2008. A mobile phone support service for sick-day management began in May 2005. Data from clinic attendees (group 1), including age, sex, diabetes duration, referral age, insulin therapy delivery, clinic attendance and HbA(1c) , were compared with clinic attendees with diabetic ketosis accessing sick-day management phone support (group 2), clinic attendees not accessing phone support and admitted with diabetic ketoacidosis (group 3) and non-clinic attendees admitted with diabetic ketoacidosis (group 4).Age was similar in all groups. Patients in group 3 had significantly shorter duration of diabetes (6.8 ± 3.1 years) than groups 1 or 2 (10.1 and 9.8 years, respectively). Diabetes control was poor in all presentations of diabetic ketoacidosis (groups 2-4, HbA(1c)97 mmol/mol,11%) and was significantly higher than clinic attendees without ketosis (HbA(1c) 70 mmol/mol, 8.6%; P0.001). There was similar attendance at the clinic across all three groups, 2.9 compared with 2.4 compared with 2.1 visits/year, respectively. Thirty-one patients accessed phone support on 83 occasions for sick-day management (mean 2.7 contacts/episode); two patients progressed to admission with diabetic ketoacidosis. Diabetic ketoacidosis admission rates in the clinic population fell significantly from baseline, 0.10 to 0.05 admissions per patient per year (P0.05) in the third year.Mobile phone support is associated with reduced progression of ketosis to diabetic ketoacidosis in young adults despite poor diabetes control.

To determine if a transition support programme for young adults with diabetes could maintain attendance at a specialist clinic, improve diabetes control and reduce acute hospital admissions with diabetic ketoacidosis (DKA) in 15-25-year-olds with Type 1 diabetes.A transition coordinator/diabetes educator arranged booking and rebooking of appointments for a young adult diabetes clinic based in an adult hospital between July 2001 and March 2006. An after-hours phone support service was initiated. Data collected included source of referral, frequency of clinic attendance and HbA1c at each visit. Numbers of admissions and readmissions with DKA, length of stay and HbA1c on admission were recorded.One hundred and ninety-one young adults were referred. HbA1c at initial referral was 9.3 +/- 2.17%. HbA1c significantly improved to 8.8 +/- 1.9% (P0.001) after a median of five visits with a statistically significant fall in HbA1c of 0.13% per visit (P = 0.01). The greatest improvements were seen in those with starting HbA1c11% (-2.5 +/- 2.3%, P0.001). Eighty-two percent had attended appointments in the last 6 months. There was a significant reduction in DKA admissions falling by 1/3 (P = 0.05), and in readmissions a significant reduction in length of stay (-3.6 days, P = 0.02), over 3.5 years.If young adults are appropriately supported in adult services, clinic attendance is maintained, diabetes control is improved and hospital admission rates with DKA are reduced. The cost savings from reduced admissions covered the costs of the programme.

Guillain–Barre syndrome (GBS) typically presents with progressive ascending paralysis and sensory loss.1 2 Both the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and dysautonomia separately have a recognised association with GBS but usually occur after the evolution of weakness.2–4 We report a patient with a rare clinical presentation of severe SIADH and dysautonomia which significantly preceded the onset of weakness and areflexia, leading to a delay in diagnosis. An 82-year-old previously active and independent woman presented with 5 days of back pain and glove and stocking paraesthesia. Her medical history included obstructive sleep apnoea, mitral regurgitation, hypercholesterolaemia, osteoporosis, gastro-oesophageal reflux disease and multinodular goitre. She had a respiratory tract infection 3 weeks earlier. She had no recent vaccinations or travel history. Her initial blood pressure was 190/90. She had one syncopal event with a corresponding drop in her systolic blood pressure to 70 mm Hg. Neurological examination demonstrated no motor or sensory deficit, and intact reflexes. Other examination and laboratory parameters were unremarkable. Given her back pain and hypertension, a CT scan was performed and excluded an aortic aneurysm or dissection. She was admitted for analgesia and observation. She had ongoing fluctuations in systolic blood pressure ranging from 60 mm Hg …

The pathophysiological mechanism of diabetes mellitus in the presence of the 3243 A-G tRNALEU(UR) mitochondrial DNA mutation is thought to result from deficient insulin secretion. However, few subjects with normal glucose tolerance have been studied to determine the sequence of events resulting in the development of diabetes mellitus.To determine whether abnormalities of insulin sensitivity, insulin secretion or glucose effectiveness are present in non-diabetic subjects with the 3243 A-G tRNALEU(UUR) mitochondrial DNA mutation.Twelve non-diabetic subjects with the mutation were compared with 12 controls, matched for age and anthropometric parameters, using both oral and intravenous glucose tolerance tests, the latter with Minimal Model analysis.Following an oral glucose load we found significantly higher blood glucose levels at 90 min and 120 min and significantly higher insulin levels at 120 min and 180 min in non-diabetic subjects with the mutation but no difference in the insulinogenic indices at 30 min and 180 min. From the intravenous glucose tolerance test there was no difference in overall glucose tolerance, insulin sensitivity, first- or second-phase insulin secretion, proinsulin secretion or glucose effectiveness. Insulin-independent glucose disposal was increased in subjects with lower insulin sensitivity and declined with increasing age in subjects with the mutation but not in controls.While there appear to be subtle defects of glucose handling in non-diabetic subjects with the 3243 mutation, these could not be explained by differences in insulin sensitivity or secretion.

Two types of retinopathy, diabetic and pigmentary, may be seen in subjects with maternal inheritance diabetes and deafness. The potential for interactions between the two retinopathies has not been explored. The mitochondrial mutation may affect development of diabetic retinopathy in subjects with MIDD by altering normal pathways of glucose metabolism. We identified five unrelated MIDD kindreds with 61 living maternal line family members. Twenty-three of the family members, 12 with diabetes mellitus and 11 without volunteered to be studied. Subjects were graded for severity of diabetic retinopathy and presence or absence of pigmentary retinopathy after slit lamp biomicroscopy, retinal photography of seven standard fields and fluorescein angiography. Blood was taken, in the fasted state, from MIDD subjects (duration of diabetes 17.0+/-6.9 yr) and non-diabetic subjects with the mutation, for assay of sorbitol and glucose and values compared with diabetic and non-diabetic control subjects without the mutation. Diabetic retinopathy was absent in 9/12 subjects (75%), with 3 having mild non-proliferative retinopathy. No one had cataract. Red blood cell sorbitol levels, adjusted for ambient blood glucose, were significantly lower in MIDD subjects compared with diabetic subjects (1.16+/-0.5 cf. 2.03+/-1.1, x 10(-3) g mmol(-1), p=0.04). Pigmentary retinopathy was present in 15 of 23 subjects, of whom 13 had some abnormality of glucose tolerance. Abnormal glucose tolerance was strongly associated with the development of pigmentary retinopathy (odds ratio 19.5, p=0.008). In conclusion, there appears to be a decreased prevalence of diabetic retinopathy and cataract in MIDD, which we propose is due to reduced glucose metabolism by the polyol pathway. Abnormal glucose tolerance increases the clinical expression of pigmentary retinopathy in subjects with a mitochondrial genome mutation. A greater understanding of the metabolic effects of mitochondrial DNA mutations has the potential to give insight into the mechanisms of diabetic retinopathy and other complications of diabetes mellitus.

Summary OBJECTIVE While menstrual disturbance is often quoted as a feature of congenital adrenal hyperplasia (CAH), little is known about the mechanism of this symptom. We set out to determine the relationship between menstrual pattern and biochemical characteristics of women with CAH due to 21-hydroxylase deficiency. PATIENTS AND DESIGN All 21 female patients with classic CAH attending the adult endocrinology clinics at The Middlesex Hospital were reviewed. Their ages at menarche and menstrual pattern were recorded and blood samples were taken in the follicular phase of the menstrual cycle when on their usual maintenance therapy. MEASUREMENTS Measurements Of serum LH, FSH, progesterone, 17α-hydroxyprogesterone, testosterone, androstenedione and plasma renin activity were recorded. Urinary steroid profiles were obtained by gas chromatography and mass spectrometry. Molecular genetic analysis of the 21-hydroxylase gene was performed on leucocyte DNA. RESULTS In the 18 patients who had spontaneous menarche the degree of menstrual disturbance and progesterone excess was related to the effectiveness of adrenal suppressive therapy. Three out of 21 patients, however, failed to experience menarche on standard medical therapy. These patients with primary amenorrhoea were characterized by reduced endometrial thickening, by non-suppressible serum progesterone concentrations despite suppression of 17α-hydroxyprogesterone levels and by the presence of progesterone metabolites in urinary steroid profiles. Molecular genetic analysis did not differentiate between patients with raised progesterone concentrations and those without. CONCLUSION A subgroup of women with congenital adrenal hyperplasia have the triad of non-suppressible serum progesterone of adrenal origin, primary amenorrhoea and Infertility due to failure of endometrial thickening. The characteristic urinary steroid profile best distinguishes this subgroup of women from others with Congenital adrenal hyperplasia and menstrual disturbance due to inadequate adrenal suppression.